Dichloromethane → 3,5'-dichloro-2'-fluoro-N-((tetrahydro-2H-pyran-4-yl)methyl)-2,4'-bipyridin-6-amine

HRID 1963810Notes

Reaction equation

HRID 1963810 reaction equation
Br[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[CH:4][C:3]=1[Cl:16].[Cl:17][C:18]1[C:19](B(O)O)=[CH:20][C:21]([F:24])=[N:22][CH:23]=1.C(Cl)Cl>COCCOC.CCOC(C)=O.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:16][C:3]1[C:2]([C:19]2[C:18]([Cl:17])=[CH:23][N:22]=[C:21]([F:24])[CH:20]=2)=[N:7][C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:5][CH:4]=1

Participants

8

Reactant 3

HCID 6344DichloromethaneHCID 44754822(5-Chloro-2-fluoropyridin-4-yl)boronic acidHCID 581273416-bromo-5-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine

Product 1

HCID 581271593,5'-dichloro-2'-fluoro-N-((tetrahydro-2H-pyran-4-yl)methyl)-2,4'-bipyridin-6-amineYield 40%

Reagents, catalysts & solvents 4

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 80711,2-DimethoxyethaneSolventHCID 8857Ethyl AcetateSolventHCID 10340Sodium CarbonateSolvent2×

Procedure

A mixture of 6-bromo-5-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine (E, 300 mg, 0.982 mmol), 5-chloro-2-fluoropyridin-4-ylboronic acid (344 mg, 1.963 mmol), PdCl2(dppf).CH2Cl2 adduct (80 mg, 0.098 mmol) in DME (4.5 mL) and 2M aqueous sodium carbonate (4.5 mL, 4.50 mmol) was heated in a sealed tube at about 103° C. for about 16 hr. The reaction mixture was cooled to ambient temperature, diluted with EtOAc (˜100 mL) and saturated aqueous sodium carbonate solution. The organic layer was separated, washed with saturated aqueous sodium carbonate solution (2×), dried over sodium sulfate, filtered off and concentrated in vacuo. The resulting resulting residue was purified by column chromatography [ISCO, SiO2, 25 g, EtOAc/heptane=0/100 to 25/75]. Fractions were combined and concentrated in vacuo providing 3,5′-dichloro-2′-fluoro-N-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridin-6-amine (140 mg) as a light brown liquid. LCMS (m/z): 356.1 [M+H]+; Retention time=0.96 min.

Workup

  1. customThe organic layer was separated
  2. washwashed with saturated aqueous sodium carbonate solution (2×)
  3. dry with materialdried over sodium sulfate
  4. filtrationfiltered off
  5. concentrationconcentrated in vacuo
  6. customThe resulting resulting residue
  7. customwas purified by column chromatography [ISCO, SiO2, 25 g, EtOAc/heptane=0/100 to 25/75]
  8. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-bf76c4b1572e4fb2b53661d042c631b9
Source dataset
uspto-grants-2013_04
Patent number
US08415381B2

Reaction notes

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